Syphilis remains an uncontrolled infectious disease globally, with high prevalence and incidence in certain high risk populations, affecting more than 20% of men who have sex with men (MSM) in Peru. Syphilis is also an important cause of neonatal morbidity and mortality, and is associated with an increased risk of acquisition and transmission of the human immunodeficiency virus. Despite its public health importance and easy medical management, the control of syphilis represents a challenge in many low and middle income countries. We have shown recently that syphilis remains poorly controlled with high rates of treatment failure and repeat infection. The incidence of syphilis in MSM in Peru is about 9 cases per 100 person-years. We are proposing a study to improve our understanding of syphilis epidemiology and molecular biology, particularly among MSM. Key in our study will be access to a population with high prevalence, incidence and repeat infection, and the collaboration of our institution with first level researchers and academic centers in the U.S. In Aim 1, we will recruit a cohort of MSM and transgender persons at high risk for syphilis, for follow-up over 24 months, to measure incidence rates of syphilis. Molecular and immunological factors will also be assessed. In Aim 2, we will determine the molecular and immunologic correlates of persistent reactivity and treatment failure by characterizing the host, pathogen and environment, and comparing measures over time and between groups. In Aim 3 we will use the findings from Aims 1 and 2 to develop an improved system/algorithm to enhance the diagnosis and management of syphilis infection, fine-tune through input from technical and community stakeholders, and design a new study to assess its effectiveness.